2466 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 15
Gademann et al.
(S)-1-Diazo-3-{[(9H-flu or en -9-ylm eth oxy)car bon yl]am i-
n o}-4-(ter t-bu toxy)p en t-2-on e (4). Fmoc-Thr(t-Bu)-OH (4.47
g, 11.26 mmol) was transformed according to the general
procedure A. The crude product was then purified by FC on
silica gel (Et2O/pentane 1:2) to give 4 (3.76 g, 80%); yellow
foam. Rf (Et2O/pentane 1:2): 0.13. [R]D ) +1.5 (c ) 1, CHCl3).
1H NMR (300 MHz, CDCl3): δ 1.08 (d, J ) 6.5 Hz, 3H, Me),
1.22 (s, 9H, t-Bu), 4.13 (br, 2H, CH2CO), 4.23 (t, J ) 6.7 Hz,
1H, CHCH2O), 4.40-4.54 (m, 2 H), 5.6 (s, 1H, CHN2), 5.82 (d,
J ) 6.5 Hz, 1H, NH), 7.30-7.43 (m, 4 arom. H), 7.61 (d, J )
7.2 Hz, 2 arom. H), 7.77 (d, J ) 7.4 Hz, 2 arom. H). 13C NMR
(75 MHz, CDCl3): δ 18.8, 28.3, 47.3, 54.8, 63.6, 66.7, 67.1, 74.7,
120.0, 125.0, 125.1, 127.0, 127.1,127.7, 127.8, 141.4, 143.8,
156.1. IR (CHCl3): 3419w, 3007w, 2977m, 2110s, 1716s,
1633m, 1497s, 1450w, 1365s, 1327w, 1248w, 1150w, 1075w,
1029w. FAB-MS: 421 [MH]+. Anal. (C24H27N3O4) C, H, N.
1371m, 1309w, 1257m, 1157m, 1087m, 1045w. FAB-MS: 1081
[2MH]+, 563 [MNa]+, 540 [MH]+. Anal. (C32H32N2O6 ) C, H,
N.
(S)-7-{[(ter t-Bu toxy-9-car bon yl]am in o}-3-{[(9H-flu or en -
9-ylm eth oxy)ca r bon yl]a m in o}h ep ta n oic Acid (10). Diazo
ketone 6 (7.40 g, 15.0 mmol) was transformed according to
general procedure B. The crude product was then purified by
FC on silica gel (AcOEt/pentane 1:1, 1% HOAc) and recrys-
talized (CHCl3/hexane) to give 10 (4.33 g, 60%); white solid.
1H NMR in agreement with the literature.10
(S)-3-{[(9′H-F lu or en -9′-ylm eth oxy)ca r bon yl]a m in o}-4-
p h en ylbu ta n oic Acid (11). Diazo ketone (7) (2.058 g, 5 mmol)
was transformed according to general procedure B. Because
of incomplete reaction (TLC-control), another 87 mg (0.39
mmol, 0.08 equiv) of CF3COOAg in 1 mL (8.9 mmol, 1.8 equiv)
of NMM were added, and stirring was continued for 12 h at
room temperature. The crude product was then purified by
FC on silica gel (CH2Cl2/MeOH 9:1) to give 7 (1.307 g, 65%);
(S)-1-Diazo-3-{[(9H-flu or en -9-ylm eth oxy)car bon yl]am i-
n o}-4-{N-[(ter t-bu t oxy)ca r b on yl]in d ol-3-yl}b u t a n -2-on e
(5). Fmoc-Trp(Boc)-OH (4.98 g, 9.49 mmol) was transformed
according to the general procedure A. The crude product was
then purified by FC on silica gel (Et2O/pentane 1:2 to 1:1) to
give 5 (2.69 g, 50%); yellow foam. Rf (Et2O/pentane 1:2): 0.16.
[R]D ) - 5.4 (c ) 1, CHCl3). 1H NMR (300 MHz, CDCl3): δ
1.66 (s, H, t-Bu), 3.17 (d, 2H, J ) 6.5 Hz, CH2-indol-3-yl), 4.20
(t, 1H, J ) 6.7 Hz, CH2CH), 4.44 (br, 1H, CHCH2O), 4.60 (br,
1H, NHCHCO), 5.12 (s, 1H, CHN2), 5.49 (br, 1H, NH), 7.23-
7.61 (m, 9 arom. H), 7.76 (d, J ) 7.5 Hz, 3 arom. H), 8.13 (d,
J ) 8.2 Hz, 1 arom. H). 13C NMR (75 MHz, CDCl3): δ 15.3,
28.2, 47.2, 54.8, 57.6, 66.9, 83.9, 115.0, 115.4, 119.0, 120.0,
122.8, 124.3, 124.7, 125.0, 125.1, 127.1, 127.7, 130.2, 135.5,
141.4, 143.7, 149.5, 155.8, 192.8. IR (CHCl3): 3423w, 3007w,
2112s, 1724s, 1638m, 1502m, 1452s, 1369s, 1258m, 1156m,
1085m, 1020w. Anal. (C32H30N4O5) C, H, N.
1
white powder. H NMR in agreement with the literature.10
N,N-P h th a lim id oca p r oic Acid (12). To a solution of
6-aminocaproic acid (43.3 g, 330 mmol) in H2O (500 mL) and
Na2CO3 hydrate (94.42 g, 330 mmol) was added N-ethoxycar-
bonyl phthalimide (72.35 g, 330 mmol). The solution was
stirred for 30 min and then acidified to pH 4 with 6 M HCl.
The resulting precipitate was collected by filtration. Drying
(h.v.) yielded 12 (71.79 g, 83%); white solid. Mp: 107-108 °C.
1H NMR (200 MHz, CDCl3): δ 1.21-1.41 (m, 2H, CH2), 1.56-
1.72 (m, 4H, CH2), 2.24-2.31 (t, J ) 7.3 Hz, 2H, CH2COOH),
3.66 (t, J ) 7.1 Hz, 2H, (Phth)NCH2), 7.75-7.86 (m, 4 arom.
H).
N,N-P h th a lim id oca p r oyl Ch lor id e (13). Compound 12
(13.83 g, 52.9 mmol) was dissolved under Ar in CH2Cl2 (200
mL) and a few drops of dioxane. Oxalyl chloride (8.75 g, 68.9
mmol) was added, and the solution was stirred at room
temperature for 4 h. The solvent was removed under reduced
pressure. Drying (h.v.) yielded 13 (14.81 g, 92%) as colorless
oil. 1H NMR (200 MHz, CDCl3): δ 1.27-1.41 (m, 2H, CH2),
1.56-1.76 (m, 4H, CH2), 2.84 (t, J ) 7.2 Hz, 2H, CH2CO), 3.61
(t, J ) 7.1 Hz, 2H, (Phth)NCH2), 7.63-7.78 (m, 4 arom. H).
(S)-7-{[(ter t-Bu toxy-9-car bon yl]am in o}-1-diazo-3-{[(9H-
flu or en -9-ylm eth oxy)ca r bon yl]a m in o}h ep ta n e-2-on e (6).
Fmoc-L-Lys(Boc)-OH (8.68 g, 18.5 mmol) was transformed
according to general procedure A. The crude product was then
purified by FC on silica gel (CH2Cl2/Et2O 6:1 f 1:1) to give 6
1
(8.08 g, 89%). Light yellow solid. H NMR in agreement with
the literature.10
(R)-4-(1-Meth yleth yl)-3-(1-oxo-5-ph th alim idoh exan oyl)-
5,5-d ip h en yloxa zolid in -2-on e (15). To a suspension of (R)-
4-(1-methylethyl)-5,5-diphenyloxazolidin-2-one (14)11 (14.27 g,
50.8 mmol) in THF (200 mL) was slowly added BuLi (37 mL,
53.25 mmol) at 0 °C (ice bath). To the resulting clear solution
was added compound 13 (17.03 g, 60.9 mmol) in one portion.
The mixture was allowed to warm slowly to room temperature
overnight, treated with saturated NH4Cl solution, and diluted
with Et2O. The organic phase was washed with 1 M HCl (2 ×
20 mL), 1 M NaOH (2 × 20 mL), and saturated NaCl solution,
dried (MgSO4), and evaporated. FC on silica gel (Et2O/pentane
1:1) afforded 15 (18.55 g, 70%); white powder. Mp: 111-112
°C. Rf (Et2O/pentane 1:1): 0.38. [R]D ) +155.45 (c ) 1.12,
CHCl3). 1H NMR (300 MHz, CDCl3): δ 0.72 (d, J ) 6.5 Hz,
3H, Me), 0.84 (d, J ) 6.8 Hz, 3H, Me), 1.23-1.31 (m, 2H, CH2),
1.50-1.65 (m, 4H, CH2), 2.70-2.89 (m, 2H, CH2CON), 3.60 (t,
J ) 7.3 Hz, 2H, (Phth)NCH2), 5.34 (d, J ) 3.4 Hz, 1H, CHi-
Pr), 7.21-7.47 (m, 10 arom. H), 7.63-7.67 (m, 2H, Phth), 7.67-
7.78 (m, 2H, Phth). 13C NMR (75 MHz, CDCl3): δ 16.4, 21.8,
24.2, 26.2, 28.3, 29.8, 34.9, 37.7, 64.5, 89.3, 123.1, 125.6, 125.9,
127.9, 128.4, 128.6, 128.9, 132.1, 133.8, 138.1, 142.4, 152.9,
168.3, 172.8. IR (CHCl3): 3011w, 2942w, 1778s, 1710s, 1493w,
1467w, 1397m, 1366m, 1175m, 1119w, 1048w. FAB-MS: 525
[MH]+. Anal. (C32H32N2O5) C, H, N.
(S)-1-Diazo-3-{[(9H-flu or en -9-ylm eth oxy)car bon yl]am i-
n o}-4-p h en ylbu ta n -2-on e (7). Fmoc-Phe-OH (20.87 g, 53.83
mmol) was transformed according to general procedure A. The
crude product was then purified by FC on silica gel (AcOEt/
hexane 3:7) to give 7 (19.11 g, 86%); light yellow solid. 1H NMR
in agreement with the literature:10 (m.p. 133-135 °C).
(R)-3-{[(9H-F lu or en -9-ylm et h oxy)ca r b on yl]a m in o}-4-
(S)-(ter t-bu toxy)p en ta n oic Acid (8). Diazo ketone 4 (3.10
g, 7.37 mmol) was transformed according to general procedure
B. The crude product was then purified by FC on silica gel
(Et2O/pentane 1:2 to 1:1) to give 8 (2.27 g, 75%); white foam.
Rf (Et2O/pentane 1:2): 0.23. [R]D ) +7.8 (c ) 1, CHCl3). 1H
NMR (300 MHz, CDCl3) δ 1.02 (d, J ) 5.9 Hz, 3H, Me), 1.20
(s, 9H, t-Bu), 2.35 (m, 1H, CH2CO), 2.61 (m, 1H, CH2CO), 3.78
(br, 1H, CHNH), 4.00 (br, 1H, CHOt-Bu), 4.23 (br, 1H,
CHCH2O), 4.35 (d, J ) 6.2 Hz, 2H, CH2O), 7.28-7.40 (m, 4
arom. H), 7.65 (br, 2 arom. H), 7.79 (d, J ) 7.4 Hz, 2 arom H).
13C NMR (75 MHz, CDCl3) δ 20.8, 31.3, 37.7, 56.7, 70.1, 71.3,
77.7, 123.4, 128.8, 130.7, 131.3, 145.2, 147.7, 148.0, 160.9,
178.1. IR (CHCl3): 3436w, 2977m, 1718s, 1507s, 1451m,
1374w, 1323w, 1256w, 1087m. FAB-MS: 434 [MNa]+, 412
[MH]+.
(S)-3-{[(9H -F lu or en -9-ylm et h oxy)ca r b on yl]a m in o}-4-
{N-[(ter t-bu toxy)ca r bon yl]in d ol-3-yl}bu ta n oic Acid (9).
Diazo ketone 5 (1.0 g, 0.182 mmol) was transformed according
to general procedure B. The crude product was then purified
by recrystallization (CHCl3/hexane) to give 9 (697 mg, 71%);
white powder. [R]D ) -12.7 (c ) 1, CHCl3). 1H NMR (300 MHz,
CDCl3) δ 1.65 (s, 9H, t-Bu), 2.33-2.45 (m, 2H, CH2CO), 2.61-
2.85 (m, 1H, CHN), 3.07-3.19 (m, 2H, CH2-indol-3-yl), 4.14-
4.25 (m, 1H, CHCH2O), 4.24-4.56 (m, 2H, CH2O), 5.66 (d, J
) 8.4 Hz, 1H, NH), 7.24-7.60 (m, 10 arom. H), 7.70-8.12 (m,
3 arom. H). IR (CHCl3): 3432w, 2982m, 1722s, 1509m, 1452m,
(R)-3-((S)-2-{[(Ben zyloxyca r b on yl)a m in o]m et h yl}-1-
oxo-3-ph th a lim idoh exa n oyl)-4-(1-m eth yleth yl)-5,5-d iph e-
n yloxa zolid in -2-on e (16). To a solution of compound 15 (4.11
g, 7.84 mmol) in CH2Cl2 (40 mL) was added TiCl4 (0.94 mL,
8.63 mmol) at -20 °C. Et3N (1.20 mL, 8.63 mmol) was added
to the yellow solution, and the resulting dark red solution was
stirred at -20 °C for 30 min before addition of a solution of
compound benzyl N-(methoxymethyl) carbamate (prepared
according to ref 11) (1.68 g, 8.63 mmol) in CH2Cl2 (17 mL) and
TiCl4 (0.94 mL, 8.63 mmol). The mixture was stirred at 0 °C
(ice bath) for 4 h and then treated with saturated NH4Cl